The biochemical, physiological, and clinical effects of Chk1 inhibitors suggest their utility in a variety of disease states in which modulation of Chk1 and control of the cell cycle is desired. See Sanchez et al., Science, 277:1497 (1997); Chen et al., Oncogene, 18:249 (1999); Lui et al., Genes Dev., 14:1448 (2000); Tenzer et al., Curr. Med. Chem. Anti-Cancer Agents, 3:35 (2003); and Mack et al., Cancer Chemother. Pharmacol., 51(4):337 (2003). Such disease states include cancers and diseases involving non-cancerous, aberrantly proliferating cells, such as psoriasis, renal disease, and systemic lupus erythematosus.
Chk1 inhibitors have been disclosed, including aryl- and heteroaryl-substituted urea compounds; methylxanthines and related compounds; ureidothiophenes; N-pyrrolopyridinyl carboxamides; antisense Chk1 oligonucleotides; Chk1 receptor antagonists; heteroaromatic carboxamide derivatives; aminothiophenes; (indazolyl)benzimidazoles; benzimidazole quinolinones; heterocyclic-hydroxyimino-fluorenes; scytoneman derivatives, such as scytonemin; heteroarylbenzamides; indazoles; indolacarbazoles; chromane derivatives; paullones; indenopyrazoles; flavones; peptide derivatives of peptide loop of serine threonine kinases; oxindoles; diazepinoindolones; pyrimidines; urea compounds; pyrrolocarbazoles; benzofuroisoindoles; and azacyclopentafluorenes.
The therapeutic benefit of Chk1 inhibitors can be achieved through administration to a subject in need thereof, but the routes of the administration and the associated vehicles used have not been sufficiently investigated. The poor solubility of many Chk1 inhibitors has impeded the development of pharmaceutically acceptable means of administering these compounds. Additionally, some Chk1 inhibitors have been shown exhibit side effects such as hemolysis in animal models. Moreover, some Chk1 inhibitors are unstable in certain formulations and can degrade to inactive, or more concerning, toxic derivatives, prior to or during administration, thereby decreasing the effectiveness of the Chk1 inhibitor for its intended purpose.
Thus, there remains a need for compositions containing Chk1 inhibitors that provide sufficient solubility and stability, while minimizing undesired side effects. The present disclosure addresses such concerns.